Division of Molecular Genetics & Cell Biology, School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore 637551, Singapore.
Nat Commun. 2013;4:2862. doi: 10.1038/ncomms3862.
Invasion of erythrocytes by Plasmodium falciparum merozoites is a complex multi-step process mediated by specific interactions between host receptors and parasite ligands. Reticulocyte-binding protein homologues (RHs) and erythrocyte-binding-like (EBL) proteins are discharged from specialized organelles and used in early steps of invasion. Here we show that monoclonal antibodies against PfRH1 (an RH) block merozoite invasion by specifically inhibiting calcium signalling in the parasite, whereas invasion-inhibiting monoclonal antibodies targeting EBA175 (an EBL protein) have no effect on signalling. We further show that inhibition of this calcium signalling prevents EBA175 discharge and thereby formation of the junction between parasite and host cell. Our results indicate that PfRH1 has an initial sensing as well as signal transduction role that leads to the subsequent release of EBA175. They also provide new insights on how RH-host cell interactions lead to essential downstream signalling events in the parasite, suggesting new targets for malaria intervention.
恶性疟原虫裂殖子入侵红细胞是一个复杂的多步骤过程，由宿主受体和寄生虫配体之间的特异性相互作用介导。网织红细胞结合蛋白同源物（RHs）和红细胞结合样（EBL）蛋白从专门的细胞器中释放出来，并用于入侵的早期步骤。在这里，我们表明针对 PfRH1（一种 RH）的单克隆抗体通过特异性抑制寄生虫中的钙信号来阻断裂殖体入侵，而针对 EBA175（一种 EBL 蛋白）的入侵抑制性单克隆抗体对信号没有影响。我们进一步表明，抑制这种钙信号会阻止 EBA175 的释放，从而阻止寄生虫和宿主细胞之间的连接形成。我们的结果表明 PfRH1 具有初始感应和信号转导作用，从而导致随后释放 EBA175。它们还提供了关于 RH-宿主细胞相互作用如何导致寄生虫中必需的下游信号事件的新见解，为疟疾干预提供了新的靶点。
